The deiodination of thyroxine (T4) to 3,5,3,'-triiodothyronine (T3) and 3,3'5'-triiodothyronine (reverse-T3, r-T3) is quantitatively its most significant pathway of metabolism. At least 70% of the T3 produced daily is derived from the peripheral-tissue deiodination of T4. Many physiologic and pathologic states in man are associated with low serum T3 concentrations. This alteration may be acute or chronic and apparently is not related to thyroid disease. The metabolic status of these patients with low T3 levels has not been elucidated, but they are generally considered to be eumetabolic; either on the basis of normal serum T4 concentrations or increased concentrations of another biologically potent thyroid hormone. One possible candidate for the latter role is triiodothyroacetic acid (Triac). This acetic acid derivative of iodotyhronine metabolism has a reported bioactivity 10-20% that of T3. To date it has not been detected in normal human serum. Animal studies demonstrate that it is produced endogenously and that a variety of tissues can produce Triac from T3. Rat liver cell nuclear receptors demonstrate similar binding affinities for T3 and Triac. These data suggest that Triac may be physiologically more important than previously considered. We intend to examine quantitatively the kinetic characteristics of Triac and Tetrac (the deaminated derivative of T4) in man. The metabolic clearance rates will be determined by kinetic methods. The daily production rates will be determined from the clearance data and the serum levels. Studies in vitro using a variety of animal tissues will elucidate the physiologic mechanisms of the deamination pathways. Studies on animal models equivalent to the clinical states associated with low serum T3 levels in man will help to elucidate the causes of this low T3 state and indicate the role of the acetic acid derivatives in maintaining a eumetabolic state in these patients.